Oral compositions for retarding the formation of dental plaque and methods of utilization thereof

ABSTRACT

New compositions effective in inhibiting the formation of dental plaque comprise an antibacterial agent in combination with an enamel conditioning agent to facilitate incorporation of the antibacterial agent into the dental enamel. A new method of inhibiting the formation of dental plaque comprises the step of applying such a composition to the oral hard tissues.

United States Patent 1 Katz [ ORAL COMPOSITIONS FOR RETARDING THEFORMATION OF DENTAL PLAQUE AND METHODS OF UTILIZATION THEREOF [75]Inventor: Simon Katz, Indianapolis, Ind.

[73] Assignee: Indiana University Foundation,

Bloomington, Ind.

[ Notice: The portion of the term of this patent subsequent to July 19,1989, has been disclaimed.

[22] Filed: Apr. 9, 1973 21 Appl. No.: 349,274

[ *July 29, 1975 7/1972 Katz 424/52 7/1972 Widder et al. 424/52 FOREIGNPATENTS OR APPLICATIONS 1,186,706 4/1970 United Kingdom 424/49 506,2916/1971 Switzerland 424/52 Primary Examiner-Richard L. Huff Attorney,Agent, or Firm-Kirkland & Ellis [57] ABSTRACT New compositions effectivein inhibiting the formation of dental plaque comprise an antibacterialagent in combination with an enamel conditioning agent to facilitateincorporation of the antibacterial agent into the dental enamel. A newmethod of inhibiting the formation of dental plaque comprises the stepof applying such a composition to the oral hard tissues.

2 Claims, No Drawings ORAL COMPOSITIONS FOR RETARDING THE FORMATION OFDENTAL PLAQUE AND METHODS OF UTILIZATION THEREOF BACKGROUND OF THEINVENTION l. Field of the Invention This invention relates to the dentalarts and more particularly to the utilization of compositions comprisingantibacterial agents and enamel conditioning agents to inhibit theformation of dental plaque.

2. Description of the Prior Art Dental plaque is a complex organic filmwhich adheres to and coats the oral hard tissues. The formation andproperties of dental plaque are extremely important in the maintenanceof oral health since plaque comprises the medium in which dental cariesand gingivitis producing bacteria grow. In fact, dental plaque iscomposed essentially of bacterial colonies growing in an interbacterialorganic matrix that provides adherence of the colonies to the teeth andgingiva and coherence of the colonies to one another. Thus, theelimination or inhibition of dental plaque is related to and beneficialin reducing the incidence of dental caries and gingival inflammation.

As is well known to those skilled in the art, dental caries is causedprincipally by dissolution of enamel in biologically produced intra-oralacids. Such biologically produced intra-oral acids primarily areproduced by some of the bacterial colonies that constitute dentalplaque. Gingival inflammation, which is the first stage of most severeperiodontal diseases is produced by inflammatory end products of plaquebacteria metabolism. Among these bacteria] metabolites one can mentionhydrolytic enzymes, endotoxins and antigens.

Thus, the elimination of the medium which comprises such caries andgingivitis producing bacteria is believed directly to affect theincidence of dental caries and periodontal disease.

The formation of dental plaque is not fully understood but it is knownto result from the growth and colonization of various strains of oralbacteria on the surface of the teeth and gingiva. Further, there isbelived to be a direct relationship between the ability of dental plaqueto induce the precipitation (crystallization) of calcium salts on thesurface of the teeth and the formation of dental calculus.

Dental calculus is a hard deposit found on the surfaces of the teethwhich results from the precipitation of calcium salts over an organicmatrix, primarily plaque. Thus, calculus can be defined as calcifiedplaque. Calculus is important to dental health since its presence isassociated with pathological changes in the bone. gingiva and othersupporting periodontel structures. Thus, the elimination and retardationof the formation of dental plaque is an important factor in dentalhygienic and health programs not only in the reduction of dental cariesand periodontal disease but also the reduction of the formation ofdental calculus.

The utilization of antibacterial agents such as atiseptics andgermicides for topical application in the oral cavity is well known inthe art. By way of explanation, an antiseptic ordinarily is consideredto be a substance which stops or inhibits the growth of micoorganismswithout necessarily killing them. In contrast, a bacteriocide orgermicide is any substance which kills or destroys bacteria. Frequentlythe difference between bacteriostatic and bacteriocidal effects is afunction of the concentration of the antibacterial agents.

Less irritating antiseptics find wide usage for topical application onthe oral mucosa for the control of minor infections and on dried mucosain preparation for needle insertion. Antiseptics too irritating for useon soft tissue find application within the tooth structure for rootcanal sterilization or cavity medication. Germicides have also beenincorporated in commercial mouthwashes, which are medicated liquids usedfor cleaning the mouth or treating disease states in the oral mucousmembrane.

Despite the'widely known use of antiseptics and germicides in the oralcavity, previous experience has failed to indicate that such materialshad any significant effect in inhibiting the formation of dental plaqueeven though dental plaque is belived to result from the colonization oforal bacteria on the surface of the teeth and gums. The reasons for thisfailure are that practically all the antibacterial agents tested so farexert their action in the oral cavity and not specifically on the toothsurface (which is where bacteria colonize) and. in addition, that theduration of the antibacterial effect is rather short, so that thebacterial population of the mouth reaches its previous values shortlyafter a con ventional antibacterial agent is applied.

SUMMARY OF THE INVENTION In accordance with the subject invention,improved compositions for dental plaque retardation and methods ofapplication thereof have been discovered. Specifically, the improvedcompositions for plaque retardation comprise a non-toxic andanti-bacterial agent and a non-toxic enamel conditioning agent, ashereinafter described, in amounts effective to'inhibit dental plaqueformation. The effect of the enamel conditioning agent is to promote theincorporation of the antibacterial agent into the dental hard tissues,thus making these tissues resistant to bacterial colonization and plaqueformation.

To be effective in plaque reduction, it was postulated that theantibacterial agent must be held by the hard tissues on the surface ofthe teeth for sufficient periods of time so that bacterial colonizationon these tissues is prevented.

Enamel conditioning agents in accordance with the invention act tosoften or loosen the crystal lattice of the dental enamel structure,thereby facilitating incorporation of the antibacterial agent into theenamel lattice. It is often desirable and advantageous to include aprecipitating agent in the present invention to facilitate and speed upthe rehardening of the enamel after treatment. Both fluorides andphosphates act as a precipitating agent and may be incoporated into thepresent invention. Fluoride ions cause a precipitation of calciumphosphate in apatite form, and thus, aid in hardening the enamel aftertreatment. Phosphate ions act to cause an over balance of theequilibrium during treatment in the oral cavity thus aid and speed upthe rehardening process of the enamel. Since certain enamel conditioningagents already incorporate fluorides and or phosphates, it is not alwaysnecessary to provide a separate precipitating agent. Other precipitatingagents include sources of ions of tin (II), calcium, aluminum, vanadium,and silicon, all of which result in precipitation and reclosure of theenamel lattice.

The foregoing compositions may be provided in combination with carrierssuitable for use in the oral cavity.

suitable carriers include water and other liquids. Other carriersinclude various compatible plastics (e.g., nylon, polyethylene,polypropylene and the like) and other materials (e.g., natural bristles,wood, etc.) which may be formed into toothbrushes or interdentalstimulators and thus utilized to apply the active agents of the presentinvention to the oral hard tissues. Also, 'other carriers include waxes,plastics or other adhesives used on dental flosses and tape, or chewinggum which contact the oral hard tissues during use or consumption.Indeed, substantially any device or implement capable of supplying theactive agents to the oral hard tissues may serve as a suitable carrierin accordance with this invention.

Thus, it is a principal object of the present invention to provideimproved compositions for plaque retardation which inhibit the formationof dental plaque on the oral hard tissues.

A further object of the present invention is to provide improvedcompositions for plaque retardation characterized by the inclusion of anenamel conditioning agent in combination with an antibacterial agentwhich inhibits the formation of dental plaque thereby reducing theincidence of dental caries and periodontal disease and the formation ofdental calculus.

A still further object of the present invention is to provide a newmethod of inhibiting the formation of dental plaque on the oral hardtissues characterized by the application of compositions including anenamel conditioning agent in combination with an antibacterial agent tothe oral hard tissues.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS This inventionconcerns the utilization of compositions which comprise a non-toxicenamel conditioning agent and a non-toxic antibacterial agent in amountseffective to inhibit dental plaque formation. The enamel conditioningagent acts to soften or loosen the crystal lattice of the dental enamel,thereby factilitating the incorporation of the antibacterial agenttherein.

Suitable non-toxic enamel conditioning agents include acids, such asorthophosphoric acid, acetic acid, boric acid, and orthosilicic acid,and calcium ion chelating agents such as fumaric acid; tartaric acid;methyliminodiacetic acid; difluoroxalatostannate (II) complexes; (e.g.,potassium difluoroxalatostannate, sodium difluoroxalatostannate, andammonium difluorokaltostannate) hydroxyethyl tetraacetic acid;diethylenetriamine pentaacetic acid; hydroxyethylene diamine triaceticacid; ethylene glycol bis (B- amimoethylene) tetraacetic acid;cyclohexane diamine tetraacetic acid; ethylenediamine tetraacetic acid(EDTA); adipic acid; glutaric acid; and polyphosphates, such as disodiumethane-l-hydroxy-l, 1- diphosphonatc (EHDP), and amonium salts ofcondensation products of ammonia and phosphorus pentoxides, e.g.',

II II l O O H4NO n n HN NH or H NOP-O-PONH r 4- 4 f 0 o YJP andmixturesthereof. Difluoroxalatostan'nate,(II) complexes, fumaric acid,Victamide, and EHDP are preferred enamel conditioning agents inaccordance with this invention.

* These complexes and their preparation are disclosed in US. Pat. No.3,678.53.

* These salts and a mode of preparation thereof are set forth anddescribed in US. Pat. No. 2,122,122. Such salts are commerciallyavailable from the Staufi'er Chemical Company under the trademark "Victamide and are hereinafter referredto by the Victamide name.

Suitable non-toxic antibacterial agents include phenols; bisphenols(such as hexachlorophene); halogenated salicylanilides andcarboxianilides [such as TBS (tribromosalicylanilide) and fluorophene(3,5- dibromo-3 -trifluoromethylsalicylanilide 1; paminosalicyclic acid;p-aminobenzoic acid; malonates; heavy metals (e.g., mercury) and anyother relatively non-toxic agent capable of retarding or inhibitingbacterial 'growth, or producing the death of bacteria. Frequently, theperformance of one or the other of these objectives can be achieved withthe same compound as a function of its concentration.

Fluorophene and TBS are preferred antibacterial agents in accordancewith this invention.

While not limited to any particular theory or mechanism of action, it isbelieved that the presence of the enamel conditioning agent in thecompositions of the present invention serves to enhance the uptake ofantibacterial agents by dental enamel in the following manner. Treatmentof the dental enamel with an enamel conditioner (i.e., acid or chelatingagent) expands the enamel crystal lattice (i.e., produces aslightdissolution of the dental enamel thereby causing a slightloosening of the crystal lattice). Antibacterial agents present in thetreatment medium thus have access not only to the surface of theenamelcrystals but also to the partially dissolved tissue, i.e.', theyare free to penetrate deeper into the enamel lattice where they aretrapped. during the reprecipitation phase of the enamel conditioningprocess. Thus, as used herein, the term enamel conditioning agent meansany calcium ion chelating agent, acid or other agent capable ofexpanding (i.e., dissolving and/or loosening) the dental enamel crystallattice to facilitate uptake of the antibacterial agent, followed by amechanism to provoke the subsequent reprecipitationland rehardening ofthe slightly dissolved tissue.

Reprecipitation of the dissolved apatite crystals and the finalretightening of the crystal lattice may be obtained in several ways, Anideal agent for reprecipitation is fluoride, which promotes thecrystallization of calcium phosphate solutions. Fluoride substitutes forOH in the apatite lattice, and produces a decrease in the unit cellparameters and an improvement in the crystallinity of the tissue. Thus,stannous fluoride, sodium fluoride and other water soluble fluorides maybe used, with the fluoride acting to cause calcium phosphate toprecipitate. Also suitable are soluble phosphates such as alkali metalphosphates and P 0 with the phosphate ions acting to force the reactionequilibrium toward rehardening of the enameLOthersuitable precipitatingagents include soluble calcium;,tin (ll), aluminum, vanadium, andsilicon ion containing sources which serve'to enhanceareclosure of thecrystal lattice. l

In the case of certainenamel conditioning agents which contain fluorideorphosphate .or other such ions, (e.g., difluoroxalatostarnate (ll)complexes, Victamide,

EHD'P and the like), 'no separate precipitating agent need be employed(i-.e., the enamel conditioning agent both loosens theenamel-crystallattice to facilitate uptake of the antibacterial agentand it returnsv the crystal lattice toits tightened configurationincorporatingv the antibacterial agent). Other ions present inthe oralenvironment (e.g., fluoride and/orstannous ;ion s) may also beincorporated, into theenamelin the same manner. l

Fluoride, phosphate, and,other pfiecipitating agents in accordance withthis invention, where required, may be provided at levels of grater than0 up to about 1.0% byweight of the composition} i When applied to theteeth, the compositions of the invention exhibit effectiveness inretarding and elimi nating the formation of dental plaque; from thedental surfaces and .contiguous gingival surfaces, thereby reducing themediain which caries and periodontal disease producing bacteria grow andfurther reducing or eliminating one of the constituentsof dentalcalculus.

The foregoing compositions comprising an enamel conditioning agent,antibacterial agent, .and, in certain cases a precipitating agent-arepreferably applied to the oral hard tissuesby means of aicarriersuitable for use in the oral cavity; Suitable carriers include, in thecase of dentifrices and prophylaxis pastes, cleaning and polishingagents and other constituents ordinarily pro.-

vi'ded insuch products. In the case of topical solutions andmouthwashes, suitable carriers include water and other liquids. Othercarriers include various compatible plastics (e.g., nylon, polyethylene,polypropylene and the like) and other materials (e.g., natural bristles,wood, etc.) which may be formed into toothbrushes or interdentalstimulators and thus utilized to apply the active agents of the percentinvention tothe oral hard tissues. Also, other carriers includewaxesand/or plastics and/or any'other adhesives used on dental flossesand tapes or chewing gum which contact the oral hard tissues during useor consumption. Indeed, substantially any device or implement capable ofsupplying the active agents to the oral hard tissues may serve as asuitable carrier in accordance with this invention.

Generally speaking, the enamel conditioning agent is present in the oralcompositions of this invention at a level of about 0.01% up to about10%, preferably about 0.1-2.5% by weight of the composition. Theantibacterial agent is present in such compositions at a level of about001% up to about 5.0%, preferably about 0.1-2% by weight of thecomposition. Where employed, the precipitating agent is present at a.level of greater than 0 up to about 1.0% weight of the composition. fa

DENTIFRICE PREPARATIONS '1 Compositions adapted for regular home-usesuch as dentifrice preparations and the like typically comprise. about20-95% by weight of a compatible cleaning and polishing agentasa carriersuitable for use in the oral cavity. The enamel conditioning agentcontent of a 6 dentifrice should be from about 0.01% up to about 5.0%,preferably from about 0.1 to 2.5 by weight of the dentifricepreparation. The antibacterial agent content should be from about 0.01%to about 5.0% and preferably from about 0.1 to 1.0% by weight.

Various compatible cleaning and polishing agents suitablefor use in thedentifrice embodiments of this invention are known in the art, includinginsoluble sodium metaphosphate, calcium pyrophosphate, calciumhydrogenphosphate dihydrate, anhydrous calcium hydrogen phosphate, andsubstantially water impervious cross-linked thennosetting highlypolymerized synthetic resins (e.g., melamine formaldehyde resins) asdescribed in US. Pat. No. 3,070,510. Preferably, zirconium silicate ormixtures of zirconium silicate with other cleaning and polishing agents(e.g., talc) as set forth and described in U.S.; Pat. -No. 3,450,813 maybe used as the cleaning and polishing agent. Also, mixtures of suchpolishing agents may also be employed. The dentifrice preparations maybe prepared in a conventional manner and will usually include additionalingredients to render the overall composition commercially acceptable toconsumers.

Dentifrices require a binder substance toimpart desired texturalproperties. Natural gum binders such as gum tragacanth, gum karaya, gumarabic,etc. and seaweed derivatives such as Irish moss and alginates,and water soluble cellulose derivatives, such as hydroxyethyl celluloseand sodium carboxymethyl cellulose can be usedfori this purpose.Desirably, those materials are employed which are mostcompatible withthe chelating agent and the antibacterial agent. Binders which have noionic groups, such as hy'droxyethyl cellulose are especially preferred.Improvements in texture can also-be attained by including an additionalmaterial such as colloidal magnesium aluminuni .-'sil icate.f Thickeningagents in an amount of from 0.5'to5.0% by weight can also be used toform a satisfactory dentifrice.

Dentifrices conventionally contain sudsin'g agents. Suitable sudsingagents include,b'ut are not limited to, water soluble alkyl sulfateshaving from 8 to l 8.carbon atoms in the alkyl radical, such as sodiumlauryl sulfate, water .soluble salts of sulfonated monoglyce'fides offatty acids having from 10 to I8 carbon atoms inthe alkyl radical suchas sodium coconut monoglyceride sulfonate, salts of fatty acid amides oftaurines such as sodium-N-methyl palmitoyl 'tauride, and saltsof fattyacid esters of isethionic.'-acid. Sudsing agents can be usedincornpositions of 'thisinvention in an amount of from; about 0.5% toabout 5.0% by weight ofthe total composition. v

It is also desirable "to'in'clude' some hum'e ctantmateria'l in adentifrice to keep it from'hardening. Materials commonly used for thispurpose include 'glyceri'ne, sorbitol; and other polyhydric alcohols.The humectants can comprise upto 35% ofthe toothpaste composition. Flvoring materials may'fbe included in dentifrice for mulations includingsmallainounts of oils of wintegre'eii and peppermint and sweeteningagents such as saccharin de xtro se, and levulose. I I i v I Preferredantiplaque dentifrice preparations are given hereinafter by way of examples are presented for the purpose of illustrationbutnot .ofliinitation,I f

EXAMPLE 1 The compatible substances previously described as.

- suitable cleaning and polishing agents for incorporation By weight indentifrice preparations may also be employed as the Fluomphene Q25cleanlng and polishing component of prophylactic Polyethylene glycol 4002.0 5 paste compositions. However, in order that the desired i i optimallevel of cleaning and polishing effectiveness be Potassium hlphtalateL200 water 250 obtalned, a different particle size and surfaceconfiguration for the substance is needed. For example, a suit- SodiumAlkyl sulfate able 'ZIICOHIUITI slllcatepreparatloll for use in a denti-Veegum 0.4 It) frice preparation is disclosed and claimed in US. Pat.

carbmXmehycemlmse No. 3,450,813, and suitable zirconium silicatecleaning Saccharrn 0.l Flavoring agent 0.7 and polrshlng agents for usein a prophylactic paste zifcqniumsilicale composition is described andclaimed in US. Pat. Nos. Calclum pyrophosphate 30.0 2 and 3.330.732.

l5 Other suitable cleaning and polishing agents include mixtures ofzirconium silicate and tin dioxide (as set forth and described in US.Pat. No. 3,378,445), lava EXAMPLE ll pumica,silica powder, calciumcarbonate, and the like. Prophylactic paste compositions in accordancewith the present invention are formulated from about 0.0l

$52 80 6 to about 10 and preferably about 0.1-2.5 of an enamel Potassiumdifluoroxolatostannate 0,3 conditioningagent and about 0.01 to about5.0% and HYdFOFthYIEHfiC'FHHCBUC acid preferably about 01-10% of ananti-bacterial agent. Potasslum Acetate 2.0 Wmr 200 The cleaning andpolishing agent serves as a carrier and Glycerin 5-0 is employed with arange of about 20 to 80% by weight I 822 depending on the particularformulations as is well Carboxymethylcellulnse 2.0 known 10 one skilledin the art.

gggfigr Y The prophylactic paste compositions are prepared in Have, aconventional manner and usually include additional Plastic abrasive 4H)ingredients that render the overall composition com- OQOO merciallyacceptable. For example, prophylactic paste com ositions t icall embodconventional com o- P YP y P nents such as .bleachlng agents, blnders,humectants, EXAMPLE lll flavoring agents and the like. Preferredprophylactic aste compositions roduced in accordance with the p n n p In n v I By Weight presentlnventlonare given herelnafter ln Examples lVHexachlorophene to V] but it should be understood that the Examples aregggfi fgfig presented for the purpose of illustration, but not of lim-Water 200 itation. Glycerin" l5.0 40 Sorbitol 15.0 EXAMPLE IV Sodiumaryl sulfonate 0.8 Veegum 0.5

1 Carhoxymethylcellulose l.5 By Weight Coloriflg g n Fluorophene 5Flavoring agent 0.8 Victamide 5.0 Saccharin zrsio. 50.0 Insoluble sodiummetaphosphate 45.0 SnO 10.0

100.00 at r 19.5

Glycerin 4.0

Sorbitol 8.0

Veegum l.0

Keltrol 1.0

PROPHYLACTIC PASTE COMPOSITIONS Saccharin 0.2

Compositions of the present invention include, In adl 0000,

dition to the described dentifrice preparations, prophylactic pastecompositions adapted for relatively infrequent application (e.g., onceor twice a year), either EXAMPLE v professionally (i.e., by a dentist ordental hygienist) or by self-application under professional supervision.Prophylactic paste composition generally differs from a Zephiran H00 0.0dentlfrrce composition in that the cleanlng and pollsh- M ethyliminodiacetic acid. 0.5 ing component thereof is more abrasive (and as are- @252? 2 8 sult, is a better tooth cleaner). Since a prophylactic(nycgrin paste composition is applied only once or twice per year, amore abrasive cleaning and polishing agent may CMC safely be employedtherein than in a dentifrice preparag r g gent 8.3 tion (i.e., if thernore abrasive cleanlng and polishing agem agent were used in adentlfrlce preparation adapted for .0000

frequent application, the agent might permanently damage the oral hardtissues).

EXAMPLE VI By Weight TBS 0.5 Fumaric acid 0.2 Potassiumdifluoroxolatostannate 2.0

, Hydrated alumina 40.0 v ZrSiO, 24.3 Water 16.0 Glycerin 4.0 Sorbitol8.0 CMC f, 1.0 Veegum 1.0 Titanium dioxide 2.0 Saccharin 0.2 Flavoringagents 0.8

OTHER COMPOSITIONS In addition to dentifrices and prophylactic pastes,the I present invention may be used in conjunction with othercompositions (e.g., topical solutions and mouthwashes) comprising enamelconditioning agents in the range of about 0.l5.0% and antibacterialagents in the range of about 0.0l-2.5% as shown in the followingExamples.

EXAMPLE VII TOPICAL SOLUTION In addition to the above carriers, thepresent invention may be used in conjunction with various other carrierswhich contact the oral hard tissues during normal use. For example,typically the bristles (either plastic or natural) of a toothbrush, thesurfaces of plastic or wooden interdental stimulator, and the surfacesof a rubber or plastic dental prophylaxis cup come into close contactwith the oral hard tissues, and thus provide a suitable carrier for theactive agents of the present invention, with such agents beingimpregnated in or coated on such carriers.

Similarly, dental flosses and dental tapes utilized to clean theinterproximal surfaces of the teeth typically include a waxy, plastic orother material which serves as a carrier for the active agents of thepresent invention. Typically, such wax may be a water insoluble wax(e.g., paraffin) or a water soluble wax (e.g., polyethylene glycol,polyethylene oxide, polypropylene oxide, methylcellulose and mixturesthereof). Plastics such as vinyl acetate .andadhesives such as polyvinylalcohol are examples of other carriers.

In the same manner, an insoluble chewing gum base may be used as thecarrier in compositions in accordance with the present invention.Chewing gums in accordance with this invention include about 0.l-2.5% byweight of an enamel conditioning agent and about 0.0l-l .0% by weight ofan antibacterial agent.

Suitable conventional stick gum bases (i.e., as opposed to bubble gumbases) include Paloja; Firm Paloja"; Berguna"; and Dreyco, all availablefrom the L. A. Dreyfus Corporation, PO. Box 500, South Plainfield,N..I., and Synthetic Base No. 2939" and Natural Base No. SC319, whichhave been obtained from the American Chicle Company, New York, NY.

In general, Firm Paloja, Synthetic Base No. 2939, Berguna, and Dreycoare preferred chewing gum bases.

Suitable bubblegum bases include: D.C."; Extra Soft; Oak; I Grande";Soft Ideal; ldeal; Model; and Ladco", all available from the L. A.Dreyfus Corporation. Bubble gums employing Oak, Soft, Extra Soft, andDC. are considered to heme preferred bubble gum bases. Chewing gumsbases are present in gums at a level of about l0-40% by weight.

Chewing gums also typically comprise excipient con-' stituents such asany of the convention flavoring and sweetening components of a level inthe range of about 4070%.by weight. Flavors such as spearmint,peppermint, wintergreen, fruit flavors, and the like may be used.Suitable sweeteners include sorbitol, corn syrup. and sugar.

Inert filling ingredients, such as mannitol, glycerin, lecithin, or thelike are provided in order to contribute to the over-allconsistency ofthecomposition.

The foregoing gum bases, excipients, and fillers are all known chewinggum constituents, and are provided at conventional levels, and thereforeper 'se form no part of the present invention.

Typical examples of exemplary chewing gums produced in accordance withthe present inventionare given in the followingExamples.

EXPERIMENTAL EVALUATIONS The physical properties and the antiplaqueeffectiveness of the oral compositions of the present invention havebeen demonstrated by laboratory studiesdesigned to measure: (1)whetheror not,the oral compositions of the present invention in factincorporate the antibacterial agent, into the dental hard tissues-(particularly en'-. amel) structure and thus render these tissuesresistant to bacterial colonization; (2).the antiplaque -effectives nessof the present invention; and (3) the toxicity of the present invention.1 i I 7 Three types of studies were conducted ,to, determine theeffectiveness of the present invention in incorporating an antibacterial.agent into dental hard' tissues; namely: a

a. chemical determination of the incorporation of the antiplaque agentinto enamel treated with the pres-- ent invention;

b. studies showing lack of bacterial colonization on dental enameltreated with this invention;

c.., studies showing the antibacterial properties of powdered dentalenamel treated with this inve'n' tion. 1n the chemical determination ofthe incorporation of the antibacterial agent into enamel, threedifferent experiments were conducted. .1

The first experiment conducted was to determinethe effect of enamelconditioning agents upon the incorporation of fluorophene into powderedenamel to establish whether or not enamel conditioning agents pro-- motethe incorporation of flurophene into powdered" enamel. Enamelwasseparatedsaccording to the procedure of Manly and Hodge,'-J.Dent.Res.18:133, 1939. Samples of 2.5 g of enamel powder were treated for fivehours with 25 ml of different fluorophene containingenamel conditioningand non-enamel conditioning systems, under constant stirring in arevolving wheel. After the treatment, the powdered enamel was separatedby filtration under suction using No. 40 Whatman filter paper and.carefully washed 3 times with 80 ml of redistilled water. The sampleswere then subjected to acetone extraction by stirring. them for 3 hoursin the revolving "wheel in 30 ml acetone. After filtration through a No.40 Whatman filterpaper, the solvent was allowed to evaporate at roomtemperature until the volume was reduced to 2.0 ml. The concentratedsolutions were then analyzed by two dimensional paper chromatography,using the following solvents: First dimension: methyl alcohol-acetone19:1; Second dimension: acetone-methyl alcohol-acetic acid 10:l0:l. A 10X 10 cm No. 5 Whatman paper was used for this analysis, the time foreach run being 15 minutes. The chromatographic pattern was depictedusing an ultraviolet light. A' run was conducted using 0.25% solution offluorophene in acetone to obtain a control pattern for fluorophenealone. The systems used in this study are as follows:

TABLE 1 TABLE :l-Continued 1n Grams Fluorophene 0.25 Distilled Water79.75 System3 I I .1 Tween 20.0

- Fluorophene 0.25 Fumaric Acid 0.15 Distilled Water 79.60 System 4Tween 80* 20.0 2 I Fluorophene 0.25 Fumaric Acid 0. l 5 SnF 0.413 r K CO H O .486 Distilled Water 78.711 System5 Tween 80* 20.0 Fluorophene0.25 Fumaric Acid 0.15 E2 0.413 K C O H O 0.486

.. 2 s 0.500 NH OH 0.500 Distilled Water 77.71 i

mani'ifacturcd hy Atlas'Chcmicul lndustrius lnc The results of this testshowed that the control 0.25% fluorophene solution gave achromatographic pattern similar to those producedby Systems 3, 4, and 5(two U.V. spots),-when subjected to the ultraviolet light. Systems 1 and2 produced a singlespot (probably due to Tween 80) which shows thatunder this experimental condition only enamel conditioningagent-containing systems produce incorporation of fluorophene intopowdered enamel. 1

The second experiment conducted was to determine the quantitative amountoffluorophene incorporated into powdered enamel when used in enamelconditioning agent containing systems. I

Ultraviolet spectrophotometry was used for the determination offluorophene removed by acetone ex traction from enamel treated withdifferent enamel conditioning and non-enamel conditioning systemscontaining fluorophene. The enamel powderto be used in this experimentwas obtained in the manner previously described. 1 I

A preweighed 0.1 g sample of fluorophene was placed in a 100 mlvolumetric flask and diluted to the mark with methyl alcohol. Duplicatespecimens of 1.0, 2.0, 3.0, 4.0, and 5.0 ml of the solution wastransferred into 150 ml beakers, and each was diluted'to approximatelyml with alcohol. The pH of one of the specimenswithin each pair wasadjusted to pH 9-10 with 0.01 N KOHIThe second specimen was adjusted topH 4-5 with 0.01 N HCl. Each speciment was then finally diluted'to mlusing a volumetric flask and methyl alcohol-.{l10ml of the firstaliquot-adjusted to pH 4-5 was placedin the 1 cm reference call of aPerkin- Elmer spectrophotometer. 1.0 mlof the specimen within the samepair adjusted to pH 9l0 was placed in In Grams the l-lcm sample cell.The differential ultraviolet ab- System I sorption curve for eachpair'ofth'e samples was run to Tween 80* 60 -determine.the-standardcurve at 295 pm (absorption Distilled Water 20.0 l I 1 System 2 maxima).Tween 80* 20.0 Results for the Standard Curve:

TABLE 11 Differential Shifted (Cor- Amount of Optical Density Opticalrected) Optical Fluorophene (pg) pH 9l0 pH 45 Density Density 3,897,54813, TABLE ll Cntinued 55.

p Differential .-Shifted c i I Amount f Optical Density Optical rected)opfi lr i -v Fluorophene (#8) pH 9-10 pH 4-5 "Density Density" 20 0.0700.065 0.005 0.0l0 30 0.075 0.065 r' 0.010 0.0l"' 40v 1 0.080 0.065 0.015i 0.020

50 l 0.085 I 0.065 0.020 x 0.025

Enamel powder samples were treatedusing the pro tus with 100 millilitersof acetone jand subjected to cedure previously described and set forthin TABLE 1. he tachlorophene' extraction for folir hours. The ali- 1.0 gof treated enamel powder was extracted for three I quots of each" werethen analyzed spectrophotohours wi h 30 ml acetoneiin a reyolving wheel-After metrically utilizing the following procedure. A2 millilicafefulfiltration through a 40 whatma" filter P ter aliquot of the acetoneextract was added to a 25 mil- P the extract was concentrated y roomtemperature liliter volumetric flask. Five milliliters of a 2% solutionevaporation to 10 ml. The pl-l of one specimen within of4-aminoantipyrine was then added. The solution was the different P wasadlacem to P" and the then diluted to the 25 milliliter mark of theflask with other to P with 9 N KOH and "Q respectivelyan ammoniumchloride-ammonium buffer solution. The Volume of specimens e l and 0.25milliliters of an" 8.0% potassium ferricyanide coho to ml m a volumemcflask m] of the P solution was mix'ed thoroughly. After 5 minutes, asam- 4-5 solution was transferred to the reference cell and P18 and ablank mp were prepared omitting the L0 ml of the pH was jansferred totone extract were transferred to a spectophotometcr sample cell. Thedifferential ultraviolet absorption celLiahdlabs-orbance a read at 475Mu The results i at was L and i g f were comparedwith a standard curveprepared with th r t ggg z i g zi izfi i 5S i known amounts ofhexachlorophene. The results of e ecor these ex eriments are shown inTABLE IV and are sults of this test are illustrated in TABLE 111. P

TABLE III ,ug Fluorophene 1 Total Fluorophene I Treatment System in U.V.Sample (rig) in 1.0 g of treated enamel I (dilution factor: 1 p v 50) l.Distilled Water-l-Tween s0 0 0- 2. 1 +0.25% Fluorophene 5 {-10 500.0 3.2 0.15% Fumaric Acid 7 i 5'1 2550.0 4. 3 +0.85% K [SnF (C O i 20 I i1000.0 i 5. 4 0.5% P20, 0.5% NH4OH. 20 I. 1000.0 I o These data indicatethat under this experimental 'condigiven in terms of total amount ofhexachlorophene detion, enamel conditioning agent containing systemsin-' tected per square centimeter of exposed enamel surcrease markedlythe incorporation of fluorophene into face. The results of these testsindicate that use of the powdered enamel. enamel conditioning dentifrice(K-82l )resulted in the In order to further determine theeffectivenessof the fiCOIPOI'atiO hekachl r phene. into he dentalpresent invention in incorporating an antibacterial enamel, whereas,neither of the non-enamel condition- I agent into the oral hard tissue,the following test preceing dentifricies (26A or 26C) to which hexachloro dure was followed (using hexachlorophene as a typical phene'hadbeen added produced incorporation of the antibacterial agent). Thelabial surface of bovine in'cisantibacterial agent into the enamel.

TABLE 1V Results 1 v r l Method of pg Hexachlorophene Product Used o VEittraction cmexposed enamel K821 H(+l.0% Hexachlorophene) I Acetone(Soxhlet) "101.89

26 A,,(+1.0% Hexachlorophene) Acetone (Soxhlet) I 0 26 C-H(-i-1.0Hexachlort'iphenel Acetone (Soxhlet) 0 ors were planed andpolished. Asurface area of thebo- The constituents of the various Products used arespecvine incisors was estimated by covering it with pieces ified inTABLE XI. of tin foil, the weight of which was compared with that Asimilar procedure was utilized to determine of a piece of tin foilhaving a known surface area. The whether a topical treatment containingan antibacterial teeth were then brushed for three minutes manuallyagent with andwithout an enamel conditioning agent withvuriousdentifrices. After brushing, the teeth .was" enhance theincorporation of hexachlorophene into thoroughly rinsed 3 times withmillilitersof distilled (,5 dental enamel. Bovine incisors were preparedessenwater to eliminate all remnants of the dentifrice. The tially asdescribed above and were given three minute teeth were then placed in aSoxhlet extraction apparatopical applications of test solutions by meansof a'cotton swab. After treatment, the teeth were thoroughlyrinsed 3times with 25 milliliters of distilled water to eliminate all remnantsof the topical solution. The teeth were then placed in a Soxhletextraction apparatus with 100 milliliters of acetone and subject tohexachlorophene extraction for 6 hours. The aliquots of extractedsolution were then analyzed for hexachlorophene as described above. Theresults of this test are illustrated in TABLE V, and these data indicatethat topical solutions containing enamel conditioning agents substanltially increase the enamel uptake of hexachlorophene per squarecentimeter of treated enamel.

TABLE VI System Bacterial (Viable) Count X Treatment Time:

5 Minutes Minutes l 20% Tween 80 in distilled water (Control)Contaminated I Contaminated 2 1 plus 0.25% Fluorophene 1 L35 3 2 plus0.15% Fumaric Acid 6.4 1.95

4 3 plus 0.8% K lsnmc om 0.73 0.00745 5 4 plus 0.5% P 0 and 0.5% NH OH16 0.25

2nd Run: Treatment time: 20 minutes I l 20% Tween 80 in distilled water(Control) I 1.275

2 1 plus 0.25% Fluorophene 4.55

Ii 2 plus 0.15% Fumaric Acid 0.23

'5 4 plus 0.5% P 0 and 0.5% NH4OH 0.23

TABLE V In order to determine the effectiveness of the present inventionin inhibiting bacterial colonization on enamel Topical TreatmentSolution pg of Hexachloroblocks brushed with a dentifrice containingenamel System Used y Percent phene P conditioning agents and anti-plaqueagents, the followtreated enamel lng studies were conducted. For thesestudies, properly Hexachlorophene 1.00 V9.95 sterilized bovine enamelsections were brushed with the W 80 experimental or control dentifrices,rinsed to eliminate Dlstllled Water 97.00 Hexachlomphem L00 483,4 pasteremnants, and placed agalnst the surface of blood g eenfia sugar platespreviously streaked with a'culture of strepumarlc cl i 7 Distilled wam9M0 tococcus mutans 6715 (NIH) After 48 and 7- hours Hexachlorophene1.00 1 5.96 of lncubatlomthe sections were aseptlcally transferred Tweeninto test tubes containing sterile Jordan medium. andMethyllmlnodlacetlc Acld .50 Dismled water 1 9650 40 lncubated foranother 120 hours. The observations In order to determine the residualantibacterial properties of powdered enamel treated with various enamelconditioning anti-plaque systems, the following studies were conducted.

Enamel powder was autoclaved to assure that the powder was steril. A 1.0g sample of enamel powder was placed into a sterile test tube, and 10 mlof the test solution was added. The test tube was. kept under constantshaking in the reciprocal shaker for 20 minutes. A second series wastested for 5 minutes. The enamel comprised the determination of presenceor absence of inhibitory halos in the agar plates and presence orabsence of bacterial growth (turbidity) in the test tubes.

The results of this study are compiled in TABLE VII and it is concludedfrom these data that dentifrices containing both an antibacterial agentand an enamel con- COCCUS.

** The composition of Jordan's medium is as follows:

powder was separated by 10 min. centrifugation (12/3 yp 5 g Solulio" d hd 3 h h h Yeast Extract 5 g MgSO .7H O 0.8 g range), an was e lmes wit astem e p osp ate KZHPQ 5 g FCSO4 7H2OO O4 g buffer (0.1N, pH 7.0, 10 mleach wash). The enamel galtcsslution 835ml MnCl .4H O 0.0189 g a z gpowder was then UBIISfG'ITCd'IIItO flasks contalnlng sutczmse' 50 gwater gs 100 ml ml of thloglycollate medlum lnnoculated wlth 0.1 m1 ofWater g.s. 1000 ml TABLE VII Enamel Anti- Number of Colonies LiquidMedium Conditioning bacterial On the Impression of Tooth On the ToothSurface Degree of Turbity After Products Agents Agents 48 Hours 72 Hours48 Hours 72 Hours 48 Hours 72 Hours Hours Control l0 l0 Uncountahle +1--H-l- Ap T.25 K [SnF (C O. )l .ZS'Z TBS 7 7 l I clear clear Ap T1.0 Same1.0%TBS 3 5 9 10 clear clear +1- Ap F.25 Same 25% V Fluorophene 2 2 l Iclear clear clear TABLE VII Continued Enamel Anti- Number of ColoniesLiquid Medium Conditioning bacterial On the Impression of Tooth On theTooth Surface Degree of Turbity After Products Agents Agents 48 Hours 72Hours 48 Hours 72 Hours 48 Hours 72 Hours 120 Hours The degree ofturbity was a visual estimate of the optical density as compared to theo a No. 66 filter. The following table indicates the relative values.

Assigned Value Clear ptical density as read in a Klett Spectrophotometerusing Klett Reading vl i s 100 1 15. 200 i 30 300 t 50 In order todetermine the effectiveness of dentifrices in accordance with thepresent invention in inhibiting the formation of in vitro formation ofdental plaque, the following test procedure was followed. Two contiguousenamel segments from bovine teeth'of equivalent surfaces wererespectively brushed with an experimental dentifrice and a control for 5minutes under 150 grams pressure. The teeth, the toothbrushes, thebrushing machine and the holders were sterilized to preventcontamination of the enamel segments. After careful rinsing of theenamel segments to eliminate all toothpaste remnants, the enamelsegments were immersed for 5 days in .lordans medium innoculated withplaqueforming streptococcus bacteria. The enamel segments weretransferred daily to freshly innoculated Jordans medium. At the end of 5days, the accumulated dental plaque was collected on aluminum planchetsand weighed immediately (wet) and after drying. TABLES VIII & IX, whichillustrate the results of that test, indicate that in each case,inclusion of an antibacterial agent substantially reduced the formationof dental plaque over a control dentifrice without an antibacterialagent. On the basis of this data, it is seen that various enamelconditioning agent-containing dentifrices having antibacterial agentsadded are significantly more'effective in reducing the plaqueaccumulation in vitro. The fact that very high reductions in plaqueaccumulation are obtained after 5 days of innoculation in an aqueousbacterial culture medium and following only one initial brushingindicates that the effect of the treatment is prolonged and leads to theconclusion that TABLE VIII Results Active Plaque Weight ComparisonPlaque Control Experiment Difference t" Ingredient (mgiSE) mg- *$.E.)(mg) Value Prevention 26C and wet 8050:28 4. 1501;40 3.900 8.02 48.45 26CH 1.0% Hexachloro phene dry 3425:48 1.1550146 2.275 3.41 66.42 K821 andwet 7.50011 1 0.075150 7.425 14.61 99.00 K821H 1.0% Hexachloro- 1 phenedry 2.325148 0025: 2.300 3.31 98.92 XIOI* and wet 6.250;"..43 0:050:506.200 9.44. 99.20 X101H 1.0% Hexachlorophene dry 3.550348 0.025150 3.5255.08 99.30 K821 and wet 5.1751148 5.675117 0.500 0.98 9.67 KT 1.0 0.1%

TBS dry 3275:49 2.125147 1.150 1.69 35.1 1

The formulae of these products are included in Table VI. 7 Products K821and X101 contain enamel conditioning agents; the control products doesnot.

TABLE IX v Products* Mean Plaque Weight and Differences ControlExperimental Plaque Control Experimental Diff. P

Condition (mg i S.E.) (mg S.E.) (r'ng) value Red.

Control 295C (Control wet 12.18107 1.60:42. 10.58 .00l 86.86 +25%Fluorophene) dry 770249 13:50 6.98 .001 90.58 K4421 295D (K4121 +25% wet6.35149 .101t49 6.25 .00l 98.43 Fluorophene) dry 4.332 249 05:50 4.28.()0l 98.84 K-82l 295E (K-821 +25% wet 6.15.1248 v1111148 5.98 .00l97.15 Fluorophene +30% dry 3.98147 .13149 3.85 .001 96.86 EHDP) K-821295G (K-82l +2571 wet 6.331149 10:49 6.23 .001 98.42 Fluorophenc +50%dry 4.25147 .05150 4.20 .001 98.82

Victamide) The formulaic ot'thcse products are included in 'l'ithlc XI.

In order to determine the effectiveness of various dentifrices inreducingthe in vivo plaque formation in rats the following testprocedure was utilized. A total of I weanling litter mate Wistar'ratswere divided randomly into equal groups according to sex'a'nd litter.Animals were weighed and ear-marked at the initiation of the studyandfinal individual body weights were determined individually prior tosacrifice. All animals were housed in raised wire cages and wereprovided with distilled water and a plaque-producing diet ad libitum.The composition of the plaque-producing diet was as follows:

Confectioners Sugar 56% Skimmed Milk Powder 28% Whole Wheat Flour 6%Brewers Yeast 4% Powdered Alfalfa 3%. Liver Powder l% 3 Sodium Chloride4 2% Prior to starting the treatment and at one weekintewvalsthereafter, the existing plaque was carefully scored. In. scoring theformation-of plaque, any soft accretion on the surface of a tooth thatwould retain basic fuchsin was consideredas dental plaque. Thequantitative estimate of the amount ofsurface and the lingual aspect offirst and second molars of both jaws was scored as follows:

Score I O the absence of dental plaque on the respective surface of atooth l the presence of dental plaque covering less than ence of dentalplaque covering between one and two thirds of the respective surface ofthe tooth.

3 the presence of dental plaque covering twothirds or more oftherespective surface of the toothf In order to convert the dentalplaque score-into a percentage score, the individual scoreof each toothwas added to get a total aminal score. This total score was divided by36 (which is the highest possible theoretical score) and the quotientmultiplied by 100. The resulting figure was considered the percentagescore for the animal in question.

The treatment consisted of twice daily applications of 1:1 slurry of therespective dentifrice-water with the aid of a cotton applicator- Eachquadrant (maxillary and mandibular) was given three strokes with theapplicator using a rolling motion to insure treatment of the buccaland'lihg'ual surfaces. The applicator was resaturated with the.treatment dentifrice slurry between quadrants-The various treatmentswere administered twicedaily for five days per week throughout a 3 weekexperimental period. The results of this test are illus- J significantlybetter than all of the others (Group 2-4).

Indeed, Group 5 had 54.0%less plaque than the next best group (Group 3),a'result that is highly significant (P O.OO5).

The formulae of the various dentifrice compositions utilized in theabove experimental evaluations are inone third of the respective surfacepl 2- thelpres- 5 cluded in TABLE XI.

TABLE X g Difference Comparison of the Dif- Group Product I Mean PlaqueScores Initial ferences with Water Initial 1 Week I 2 Weeks 3 Weeks 3'Weeks Control After 3 Weeks v I %Diff. P

l Distilled water 4. l 7i l .02 33.39122) 502811.84 69.25fl.89 650913.232 26C (Control) 3.47: .83 26.33-12.75 35.47il.l1 4l.8lil.ll 38.33:l.204l.ll 0.00l 3 26 CF (Control 4.03il.00 l4.44+2.7() 22.22fl04 26.67fl.4822.64fl.33 65.22 0.00l

Fluorophene) 4 K-82l (Control 3.20:1.02 22.22fl.5l 25.28-13.27, 40.l3'-l.73 36.94fl.l0, -43.25 0.00l

enamel condition agent) i I 5 KF.25A (K-82l .25% 3.75:1.20 11.3812627.78fl.69 l4.l7i3.33 l0.4l :'3.24 -83.99 0.00l

Fluorophene) (Control enamel 7 conditioning antiseptic agent) Theformulae of these products are included in Table VI.

TABLE XI FORMULAE FOR DENTIFRICES CONTAINING DIFFERENCE COMBINATIONSYSTEMS Group Constituent 26C K82l 295-C 295-D 295-E 295-G X101 KF.25KTI .0

Anti-Bacterial System v a I Fluorophene .25 .25 .25 .25 .25 TBS L00Enamel Conditioning System Victamide g r r 5.00 3.470 H Na EHDP 3.00 KOxalate .486 .486. .486 .486 .486 .486 Fumaric Acid I .l50 .150 .l50.l50 .l50 .l50 Precipitating System SnF .413 .413 1.413 .413 .413 .4l3BO /Water .500 50/500 .50/500 .50/5.00 .500 .500 AIF 31-1 0 0.243Abrasive System l I v Ca P- ,O (Improved) 36.90 30.00 30.00 30.00 30.0033.00 30.00 30.00 ZrSiO, (Excellopax) I230 40.00

(11 F 0 (Regular) 4333 I000 10.00 I000 ll.00 I000 I000 TABLE XIContinued FORMULAE FOR DENTIFRICES CONTAINING DIFFERENCE COMBINATIONSYSTEMS Group Constituent 26C K821 295-C 295-D 295-E 295-G X 101 KF.25KT1.0

Excipients Water 22. I 18.501 19.50 10.951 11.821 10.82 20.987 22.5022.551 Glycerine 10.00 10.000 18.00 18.00 14.13 13.13 10.000 19.30118.000 Sorbitol 20.00 15.000 .00 15.00 15.00 15.00 16.000 10.000 10.000Na A.S. .69 1.200 1.20 1.20 1.20 1.20 1.20 Veegum F. .40 .500 .50 .50.50 .50 .50 0.50 0.50 C.M.C. (7HOF) 1.50 1.000 1.00 1.00 1.00 1.00 1.001.00 1.00 Saccharin-Na .12 .200 .50 .50 .50 .50 .20 0.60 0.60 Flavor .85.850 .85 .85 .85 .85 .85 0.40 0.40 Polyethylene Glycol 400 2.00 2.002.00 2.00 2.00 2.50 Monogl ceride Sulfonate 0.81 Buffer ystem K -acidPhtalate 1.20 1.200 1.20 1.20 1.20 1.20 1.20 1.20 1.20 Color (blue) .15.300 .20 .20 NILOH/Water .500 .50/1.50 .50/1.50 .50/1.50 .500 .500

Thus, the enamel conditioning antibacterial agent containingcompositions of this invention and the methods for their use provide astriking advance over prior art compositions in their prevention andcontrol of dental plaque.

In order to determine the toxicity of the antibacterial agents used inthe above studies the effects of dentifrice preparations containingfluorophene and TBS and mixtures thereof at the upper level ofconcentration of the present invention on the oral mucosa of rats wasdetermined using conventional procedures. These studies concluded thatboth fluorophene and TBS have a high margin of safety and aresubstantially less toxic than hexachlorophene, a commonly used agent inmouthwashes. For example, the LD for 100% active TBS is 570 mg/kgwhereas the LD for hexachlorophene is 125 mg/kg when tested undersimilar conditions. Further, a force fed diet of 2.0 g/kg/body weight offluorophene in a corn oil suspension to five adult mice caused nodeaths. Thus, it should be apparent that TBS and fluorophene aresubstantially less toxic than the commonly orally utilized antibacterialagent hexachlorophene.

I claim:

1. A method of removing dental plaque from and inhibiting the formationof dental plaque on dental enamel comprising the application thereof ofa composition comprising:

about 00-50% by weight of a non-toxic antibacterial agent selected fromthe group consisting of hexachlorophene, tribromosalicylanilide. 3,S-dibromo- 3' trifluoromethyl-salicylanilide, p-aminosalicyclic acid,and p-aminobenzoic acid; and 0.01-l0% by weight of fumaric acid.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 'g gq'754g Dated Julv 29, 1975 Inventor(s) Simon Katz It'is certified thaterror appears in the above-identified patent and that said LettersPatent are hereby corrected as shown below:

Column 3, line 56 insert asterisk after "complexes" line 57"diflourokaltostannate" should read diflouroxalatostannate Column 5,line 30 insert "an" before "antibacterial" line 42 "percent" should readpresent Q Column 10, line 6 "o.1-2.5%" should read 0.01-2.5%

Column 12, line 47 "was should read were Column 20, line 8 "aminal"should read animal Column 22, line 21 "0.050%" should read 0.0l50%gigncd and Scaled this fourteenth Day 0f October 1975 [SEAL] Attest:

O RUTH c. MASON c. MARSHALL DANN Arresting Officer Commissioner ofParents and Trademarks

1. A METHOD OF REMOVING DENTAL PLAQUE FROM AND INHABITING THE FORMATIONOF DENTAL PLAQUE ON DENTAL ENAMEL COMPRISING THE APPLICATION THEREOF OFA COMPOSITION COMPRISING: ABOUT 0.0-5% BY WEIGHT OF A NON-TOXICANTIBACTERIAL AGENT SELECTED FROM THE GROUP CONSISTING OFHEXACHLOROPHENE, TRIBROMOSALICYLANILIDE, 3, 5-DIBROMO-3 3''TRIFLOUROMETHYLSALICYLANILIDE, P-AMINOSALICYCLIC ACID, ANDP-AMINOBENZONIC ACID, AND 0.01-10% BY WEIGHT OF FUMARIC ACID.
 2. Amethod of removing dental plaque from an inhibiting the formation ofdental plaque on dental enamel comprising the application thereto of acomposition comprising: about 0.01-50% by weight of a non-toxicantibacterial agent selected from the group consisting ofhexachlorophene, tribromosalicylanilide, 3, 5-dibromo-3''trifluoromethylsalicylanilide, p-aminosalicyclic acid, andp-aminoaobenzoic acid; and 0.01-10.0% by weight of adifluoroxalatostannate (II) complex.